-
Journal of Clinical and Experimental... 2022Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however...
BACKGROUND
Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients.
METHODS
HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL ( = 151) were previously randomised 1:1:1 for peg-IFN 180 μg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time.
RESULTS
Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly ( = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups ( = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups.
CONCLUSIONS
This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.
PubMed: 35677522
DOI: 10.1016/j.jceh.2021.12.011 -
Frontiers in Chemistry 2022Compounds with a phosphonate group, i.e., -P(O)(OH) group attached directly to the molecule a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various... (Review)
Review
Compounds with a phosphonate group, i.e., -P(O)(OH) group attached directly to the molecule a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called "open-ring" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).
PubMed: 35668826
DOI: 10.3389/fchem.2022.889737 -
Archives of Virology Aug 2022The aim of this study was to evaluate plasmatic and urinary therapeutic drug monitoring (TDM) of tenofovir disoproxil fumarate (TDF) in a cohort of patients with chronic...
The aim of this study was to evaluate plasmatic and urinary therapeutic drug monitoring (TDM) of tenofovir disoproxil fumarate (TDF) in a cohort of patients with chronic hepatitis B (CHB). In 68 enrolled patients, the estimated glomerular filtration rate (eGFR) was 68 mL/min in naive subjects, while in adefovir dipivoxil (ADV)-pretreated patients, it was 55.5 mL/min (p < 0.001). The HBV E genotype was associated with lower TDF levels (β = -0.698, p < 0.001). The urinary TDF concentration was associated with ADV pretreatment (β = 0.829, p < 0.001). Determination of urinary concentrations of TDF may be useful in the clinical management of older CHB patients and those with previous treatment with ADV.
Topics: Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Hepatitis B virus; Hepatitis B, Chronic; Humans; Tenofovir; Treatment Outcome; Viral Load
PubMed: 35598207
DOI: 10.1007/s00705-022-05466-y -
Frontiers in Medicine 2022Serum hepatitis B virus pregenomic RNA (HBV pgRNA) is a potential biomarker that is correlated with covalently closed circular DNA. The long-term dynamics of HBV pgRNA...
Serum hepatitis B virus pregenomic RNA (HBV pgRNA) is a potential biomarker that is correlated with covalently closed circular DNA. The long-term dynamics of HBV pgRNA in patients with chronic hepatitis B need to be explored. One hundred naïve nucleos(t)ide analog-treated patients with chronic hepatitis B were enrolled to analyze the dynamics of HBV pgRNA over 9 years. The positive rates of HBV pgRNAs declined gradually and showed biphasic kinetics. Serum HBV pgRNA levels in patients treated with entecavir became negative later than those treated with adefovir or lamivudine. Patients who remain positive for HBV pgRNA after 9 years of treatment may have higher viral transcription efficiencies. The reverse transcription efficiency of hepatitis B e-antigen (HBeAg)-positive patients was higher than that of HBeAg-negative patients at baseline and showed no difference after 24-week nucleos(t)ide analog treatment. The trajectory of serum HBV pgRNA-negative transformation differs in patients with different characteristics. Long-term dynamic monitoring of serum HBV pgRNA levels has significance in hepatitis B treatment.
PubMed: 35572978
DOI: 10.3389/fmed.2022.851717 -
Antiviral Therapy Apr 2022Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was... (Review)
Review
Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was limited to two therapeutic modalities, either interferon, which carried significant side effects and was efficacious in a minority of patients, or lamivudine which showed no durable effects with short-term use and a high rate of resistance with long-term use. Adefovir was found to be effective in suppressing viral replication and in resolving the hepatic inflammation associated with hepatitis B with only rare instances of resistance. In this article, we appreciate John Martin's contribution to science and medicine as we review the landmark trials of adefovir that brought forth a new era of treatment of Hepatitis B.
Topics: Adenine; Drug Resistance, Viral; Hepatitis B; Humans; Lamivudine; Organophosphonates
PubMed: 35499182
DOI: 10.1177/13596535211067605 -
Hepatology Research : the Official... Jul 2022Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed...
BACKGROUND & AIMS
Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients.
METHODS
A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy.
RESULTS
The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 log IU/ml in ETV and ADV/TDF groups, respectively (p = 0.0004). Higher serum IFN-λ3 levels were observed in ADV/TDF group compared with ETV group during treatment (p < 0.001). Serum IFN-λ3 levels showed negative correlation with HBsAg reduction in ADV/TDF group (r = -0.386, p = 0.038) at week 48. Nucleotide analogs (ADV/TDF) treatment has associated factors with -0.3 log HBsAg decline at 1 year, -0.5 log HBsAg decline at 3 years, and -0.8 log HBsAg decline at 5 years after NAs treatment on multivariate analysis.
CONCLUSIONS
Nucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.
PubMed: 35352445
DOI: 10.1111/hepr.13768 -
Biomedicines Jan 2022Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B...
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient's serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
PubMed: 35203489
DOI: 10.3390/biomedicines10020282 -
European Journal of Gastroenterology &... May 2022Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The development of chronic hepatitis B (CHB)-related HCC can be attributed to continuous... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The development of chronic hepatitis B (CHB)-related HCC can be attributed to continuous hepatitis B virus (HBV) infection. It is crucial to identify and monitor patients with CHB at high risk of HCC occurrence so that HCC can be detected early and the patients are able to receive effective treatment promptly to increase the survival rate and improve prognosis.
AIM
This study aimed to verify hepatitis B-related hepatocellular carcinoma predictive models to evaluate the risk of HCC in patients with liver cirrhosis under antiviral treatment.
METHODS
Patients with HBV-related compensated cirrhosis were treated with lamivudine and adefovir randomly, and then with a combination of two drugs at different time points based on the virologic response. Patients with HCC occurrence during follow-up were categorized as HCC group, whereas others as control group. They were further divided into 2-year HCC, 2-year control, 5-year HCC, and 5-year control groups according to the observation time. The operating curves of the patients were used to verify models before and after antiviral treatment.
RESULTS
Using the baseline as a parameter, the area under the curve (AUC) of risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B) after 2 and 5 years was 0.863 and 0.797, respectively. The AUC after 2 and 5 years was 0.839 and 0.747, respectively, for guide with age, gender, HBV DNA, core promoter mutations and cirrhosis (GAG-HCC) and 0.741 and 0.748, respectively, for Taiwanese HBV cohort (TW1). Using 48 weeks as the parameter, it has an optimal critical value of 8 points. The AUC of REACH-B after 2 and 5 years was 0.738 and 0.721, respectively.
CONCLUSION
REACH-B can predict the risk of HCC occurrence in patients with compensated liver cirrhosis before and after antiviral treatment. GAG-HCC and TW1 could predict the risk before antiviral treatment.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Liver Neoplasms
PubMed: 35170528
DOI: 10.1097/MEG.0000000000002302 -
Journal of Pharmaceutical and... Apr 2022Maillard degradation products may lead to a decrease in active pharmaceutical ingredients and an increase in harmful substances. In this study, five acyclic nucleoside...
Maillard degradation products may lead to a decrease in active pharmaceutical ingredients and an increase in harmful substances. In this study, five acyclic nucleoside antiviral drugs (adefovir dipivoxil, famciclovir, tenofovir dipivoxil, acyclovir, and ganciclovir) were studied. Compatibility of APIs and lactose was performed, and the Maillard reaction products were monitored by HPLC-photodiode array detection and UHPLC-ESI-MS. Eight Maillard reaction products were detected, of which six were found to be new stable compounds (impurities 1-6) and were purified and identified by NMR spectroscopy. Moreover, the six new impurities were analyzed by MS/MS, and their mass spectrometric fragmentation mechanisms were proposed. The loss of a neutral fragment at 282 Da by the fragmentation of the lactose moiety was observed in the tandem mass spectra of all the impurities. This is the first systematic study of the Maillard reaction in the case of acyclic nucleosides antiviral drugs, and it has achieved good results. The results will be helpful for understanding the mass spectrometric fragmentation mechanisms of Maillard reaction products and the stability of acyclic nucleosides, and will provide suggestions for maintaining the stability and optimizing the storage and transportation conditions of these drugs.
Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Maillard Reaction; Nucleosides; Tandem Mass Spectrometry
PubMed: 35134603
DOI: 10.1016/j.jpba.2022.114637 -
Toxicology Letters Apr 2022Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV...
Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV accumulated in the renal interstitium and caused renal interstitial fibrosis when Oat1/3 were inhibited by OATs inhibitor probenecid for long-term. Mast cells (MCs) in the interstitial space are considered to be key drivers of renal fibrosis. The current work investigated the effect of ADV on MCs in vitro and during the development of interstitial fibrosis in rats. Results indicate that ADV triggers chymase release from cultured RBL-2H3 mast cells in a time-and concentration-dependent manner. Angiotensin II (Ang II) in renal interstitium is generated mainly by chymase, renin and other products released from MCs, and has a direct effect on fibrosis through the angiotensin receptor. The concentrations of Ang II and fibrosis was significantly increased after administration of ADV alone or with probenecid for 4 weeks. The MCs membrane stabilizer sodium cromoglycate (SCG) and the angiotensin receptor antagonist Valsartan (VAL) could ameliorate ADV-induced nephrotoxicity. Additionally, SCG or VAL could reduce the accumulation of ADV in the renal interstitium by upregulating the expression of Oat1/3 and multidrug resistance-associated protein 4. Therefore, ADV accumulation in the renal interstitium could promote the degranulation of interstitial MCs and drive the development of renal fibrosis. SCG or VAL could ameliorate ADV-associated fibrosis by decreasing degranulation of MCs and accelerating renal clearance of ADV.
Topics: Adenine; Animals; Cell Degranulation; Disease Models, Animal; Fibrosis; Humans; Kidney Diseases; Kidney Tubules; Male; Mast Cells; Organophosphonates; Rats
PubMed: 35114312
DOI: 10.1016/j.toxlet.2022.01.018